Facile Synthesis of Stereodefined α-Iodovinyl Sulfoxides, Versatile Platform to Trisubstituted Olefins

Article abstract of DOI:10.1055/s-0035-1561654

Stereodefined α-iodovinyl sulfoxides bearing a sulfinyl group and an iodo group were prepared by a one-pot iodination/Horner-Wadsworth-Emmons reaction protocol. This reaction can be applied to a wide range of aldehydes, and further application was demonstrated.

Full text of DOI:10.1055/s-0035-1561654

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
S. Jung et al.
Letter
Synlett
Facile Synthesis of Stereodefined α-Iodovinyl Sulfoxides, Versatile
Platform to Trisubstituted Olefins
Sunna Jung
Yasuyuki Ueda
Keisuke Suzuki
Ken Ohmori*
Department of Chemistry, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro, Tokyo 152-8551, Japan
kohmori@chem.titech.ac.jp
Received: 06.04.2016
1) Synthesis of carba-paracyclophane
Accepted after revision: 09.05.2016
Published online: 01.06.2016
DOI: 10.1055/s-0035-1561654; Art ID: st-2016-u0238-l
RO
RO
Abstract Stereodefined α-iodovinyl sulfoxides bearing a sulfinyl group
and an iodo group were prepared by a one-pot iodination/Horner–
Wadsworth–Emmons reaction protocol. This reaction can be applied to
a wide range of aldehydes, and further application was demonstrated.
+
I
B
B
S
O
OR
OR
x 2
Ar
III
I
II
Key words sulfoxides, vinyl iodide, vinyl sulfoxides, sulfinyl phospho-
nates, trisubstituted olefins, olefination, Horner–Wadsworth–Emmons
reaction, halovinyl sulfoxides
2) Synthesis of side-chain unit III
Horner–Wadsworth–Emmons
Reaction
H
O
O
O
α-Halovinyl sulfoxides are useful building blocks in or-
ganic synthesis.1 For example, they have been used as pre-
cursors of vinylidene carbene species for various synthetic
transformations,2 and also as a platform for the stereoselec-
tive synthesis of hetero- and carbocyclic compounds.3 Al-
though further potential utilities are expected, the existing
synthetic approaches to their availability have been limited
in terms of synthetic efficacy and stereoselectivity.
In our recent study on the modular synthesis of planar
chiral carba-paracyclophanes (Scheme 1), we employed
stereodefined α-iodovinyl sulfoxide III as a building block,
which was prepared by exploiting iodo-sulfinylphospho-
nate V for the Horner–Wadsworth–Emmons (HWE) reac-
tion with aldehydes.4 Recognizing the potential utility of III
in broader sense of organic synthesis, we became interested
in addressing the scope and limitation of the above-stated
preparative method.
In this communication, we report a synthetic protocol
for the highly Z-selective synthesis of α-iodovinyl sulfox-
ides from various aldehydes. In particular, the protocol has
been made convenient by the in situ generation of V by
iodination of phosphonate followed by HWE reaction with
aldehydes. The details of this optimization processes are
now disclosed.
S
(R'O)2P
S
+
O
III
R
R
Ar
Ar
I
I
IV
V
Scheme 1 Use of α-halovinyl sulfoxides in carba-paracyclophane syn-
thesis
Scheme 2 illustrates the preparation of iodo-phospho-
nates 4a (R = Me) and 4b (R = i-Pr). Upon treatment of An-
dersen’s sulfinate5 (2) in THF with two mole equivalents of
the anion, generated from dimethyl methylphosphonate
(1a) or diisopropyl methylphosphonate (1b) by treatment
with n-BuLi at –30 °C, the corresponding sulfinyl-phospho-
nates 3a and 3b were obtained in 75% and 95% yield, re-
spectively.6 Iodination of phosphonates 3a and 3b was car-
ried out by using iodine in the presence of K2CO3 in metha-
nol, giving iodo-phosphonate 4a and 4b in 85% and 90%
yield, respectively. However, these compounds are unstable
because the carbon–iodine bond is labile and easily cleaved
during workup (10% Na2S2O3) and purification.7 In addition,
4a and 4b gradually decomposed even when stored in the
refrigerator. Therefore, freshly prepared 4a and 4b were
needed to be employed in the HWE reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
S. Jung et al.
Letter
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to a sulfinyl group appears at a lower field compared to that
of the trans counterpart (Figure 1, a). By considering this
general tendency, the major isomer of 6 was assigned to be
Z, while the minor isomer was assigned to be E.12
n-BuLi
O
(2.2 equiv)
(RO)2P Me
THF
–30 °C, 30 min
O–
S+
O
(2.0 equiv)
1a (R = Me)
1b (R = i-Pr)
(RO)2P
p-Tol
high field
THF
(a)
3a (R = Me): 75%
3b (R = i-Pr): 95%
low field
–30 °C, 0.5 h
O–
S+ p-Tol
H
O
H
O
S
R'
Ar
R
R
Ar
O–
S+
S
O
(RO)2P
O
I
2 (0.9 equiv)
K2CO3
R'
2
trans relation
cis relation
p-Tol
MeOH
I
(b)
0 °C, 0.5 h
4a (R = Me): 85%
4b (R = i-Pr): 90%
δ 7.07
δ 6.85
O–
S+
H
H
MeO OMe
H
MeO OMe
Scheme 2 Synthesis of iodophosphonates 4a and 4b
I
p-Tol
H
I
S+
p-Tol
O–
Having iodo-phosphonates 4a and 4b in hand, the HWE
reaction with aldehyde 58 was examined by the combined
use of LiCl and organic bases (Scheme 3).9 As an initial at-
tempt, the reaction of methyl derivative 4a was examined
by using Hünig’s base, giving the desired product 6 in 22%
yield with poor stereoselectivity (Scheme 3, entry 1). By us-
ing 1,8-diazabicylo[5.4.0]undec-7-ene (DBU), the yield was
improved to 68%, albeit poor stereoselectivity (Scheme 3,
entry 2). In contrast, the reaction of isopropyl derivative 4b
with Hünig’s base showed excellent stereoselectivity
(Scheme 3, entry 3).10 Furthermore, use of DBU gave 6 in
better yield (60%) without any decrease in the stereoselec-
tivity (Scheme 3, entry 4).
Z-6 (major)
E-6 (minor)
Figure 1 Stereoidentification of vinyl sulfoxides
We next screened bases to improve the yield in the re-
action of isopropyl derivative 4b (Scheme 4). The use of
1,1,3,3-tetramethylguanidine (TMG) as a base gave the de-
sired product in 74% yield with an excellent Z/E selectivity
(Scheme 4, entry 1). When 1,5,7-triazabicyclo[4.4.0]dec-5-
ene (TBD) was used as the base, product 6 was obtained in
comparable yield (Scheme 4, entry 2). Furthermore, use of
excess 4b (1.5 equiv) over aldehyde 5 resulted in the com-
The Z/E stereochemistry of 6 was assigned by the 1H
NMR chemical shift of the vinyl proton according to the lit-
erature.11 The signal of a vinyl proton with cis relationship
O–
O
(i-PrO)2P
S+
p-Tol
O–
S+
I
MeO OMe
H
base, LiCl
4b
O–
S+
p-Tol
MeCN
rt, 10 min
O
(RO)2P
I
H
MeO OMe
H
Z-6
p-Tol
O–
S+
O
+
I
MeO OMe
H
4a (R = Me)
4b (R = i-Pr)
5
MeO OMe
(1.0 equiv)
base, LiCl
p-Tol
I
H
MeCN
rt, time
I
S+
Z-6 (major)
H
O
p-Tol
MeO OMe
H
O–
+
E-6
MeO OMe
5 (1.2 equiv)
I
yield / %
74a
Z/E
94/6
93/7
98/2
94/6
entry
base
TMG
TBD
TBD
DBUc
4b
1.0
1.0
1.5
1.0
5
H
S+
p-Tol
1.2
1.2
1.0
1.2
1
2
3
4
O–
E-6 (minor)
73a
yield / %
Z/E
62/38
63/37
93/7
entry
time / min
R
base
i-Pr2NEt
DBU
81b
22
68
31
60
60
10
60
10
1
2
3
4
Me
Me
i-Pr
i-Pr
60a
N
a) Based on 4b, b) Based on 5
c) See Scheme 3, entry 4
N
N
N
N
i-Pr2NEt
DBU
N
NH
N
H
94/6
DBU
TBD
TMG
Scheme 3 HWE reaction with iodo phosphonates 4a,b and aldehyde 5
Scheme 4 Optimization of the reaction conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
S. Jung et al.
Letter
Synlett
plete consumption of aldehyde 5, giving 6 in high yield
(Scheme 4, entry 3).
Table 1, entries 3, 4) and furfural (11, Table 1, entries 5, 6),
worked well. When TBD was used as a base, the products 10
and 12 were obtained in 71% yield (Table 1, entry 3) and
85% yield (Table 1, entry 6), respectively, with excellent Z
selectivities. In contrast, use of DBU decreased the Z/E se-
lectivity to 77:23 (Table 1, entry 4) or 90:10 (Table 1, entry
5), though the yields were good. The reaction of conjugated
aldehyde 13 gave the desired trisubstituted olefin 14 in ex-
cellent yield with perfect Z selectivity in both cases of DBU
(Table 1, entry 7) and TBD (Table 1, entry 8). Unfortunately,
α-methyl cinnamaldehyde (15) resulted in low yield (Table
1, entries 9, 10). Moreover, branched aliphatic aldehydes 17
and 19 gave only moderate yields with the significantly de-
creased stereoselectivities (Table 1, entries 11–14). In addi-
tion, this protocol turned out to be inapplicable for ketone
such as 2116 (entries 15, 16), indicating a limitation of this
procedure toward tetrasubstituted olefins.
Although an optimal set of reaction conditions was thus
secured, a difficulty that still remained was the instability
of iodo-sulfinylphosphonate 4b. To resolve this issue, a one-
pot protocol was examined to generate 4b in situ, followed
by HWE reaction (Scheme 5).13 Upon treatment of phos-
phonate 3b with TBD and LiCl in MeCN, I2 was added at
room temperature.14 After consumption of 3b and genera-
tion of 4b assured by TLC monitoring (3b: Rf = 0.40, 4b: Rf =
0.58, EtOAc), aldehyde 5 was added. Further stirring for ten
minutes at room temperature gave α-iodovinyl sulfoxide 6
in 94% yield with excellent stereoselectivity (Z/E =97:3,
Scheme 5, entry 1). Comparably, when DBU was employed,
a high yield (86%) and excellent Z-stereoselectivity (Z/E =
97:3, Scheme 5, entry 2) resulted, while the use of TMG
gave poor yield (Scheme 5, entry 3).
Some utility of α-halovinyl sulfoxide in the synthesis of
trisubstituted olefin was demonstrated by successive cross-
coupling and sulfoxide–lithium exchange followed by trap-
ping with electrophile (Scheme 6). The cross-coupling reac-
tion of 10 with p-methoxyphenylboronic acid by using
Pd(PPh3)4 and K3PO4 gave 22 in stereospecific manner (70%
yield). Sulfoxide–lithium exchange17 of 22 with t-BuLi fol-
lowed by the trapping with DMF gave trisubstituted olefin
23 in 73% yield. The diagnostic NOE correlation between the
vinyl proton and the formyl group verified the E stereo-
chemistry of 23. This result shows potential utility of α-
halovinyl sulfoxides for the preparation of various trisubsti-
tuted olefins with a high stereoselectivity.
I2
O–
O–
S+
O
O
LiCl, base
(RO)2P
S+
(i-PrO)2P
Ar
MeCN
p-Tol
I
rt, 5 min
3b (1.5 equiv)
4b
H
MeO OMe
H
O
O–
S+
5 (1.0 equiv)
MeO OMe
H
p-Tol
I
Z-6
entry
base
TBD
DBU
TMG
yield / %
Z/E
97/3
97/3
96/4
1
2
3
94
86
44
sulfoxide–lithium
O–
S+
O–
S+
exchange
cross–coupling
R''
Scheme 5 Optimization of conditions by varying bases
R
p-Tol
R
p-Tol
R
I
R'
R'
A
B
C
This one-pot protocol would be useful for the prepara-
tion of various α-iodovinyl derivatives, and for the large-
scale preparation, DBU (less expensive base) is more attrac-
tive. Indeed, when the same reaction was conducted with
DBU on a 16 g scale, the desired product 6 was obtained in
82% yield without any loss of the stereoselectivity. Charac-
teristics of this protocol are: 1) the one-pot procedure
avoids tedious handling of iodo-phosphonate, 2) excellent
Z/E selectivity, 3) use of inexpensive base (DBU), in particu-
lar for the large-scale synthesis.
We next focused on the scope of the reaction, employ-
ing several carbonyl compounds (Table 1). For comparison,
DBU and TBD were employed as the base. With DBU, the
stereoselectivity was poor in some cases, which can be
compensated by the use of TBD.15
O–
S+
O–
p-MeOC6H4B(OH)2
Pd(PPh3)4
S+
K3PO4
p-Tol
p-Tol
I
DME, H2O
reflux, 1 h
10
70%
OMe
22
t-BuLi
CHO
NOE
H
then DMF
H
THF
–78 °C, 5 min
73%
Ph
O
Ar
OMe
23
Hydrocinnamaldehyde (7) gave the corresponding prod-
uct 8 in high yields with excellent Z selectivities (Table 1,
entries 1, 2). Aromatic aldehydes, such as benzaldehyde (9,
Scheme 6 Further transformation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
S. Jung et al.
Letter
Synlett
Table 1 Substrate Scope
I2
O–
S+
O
O–
S+
LiCl, base
O
(RO)2P
O–
S+
Ar
(i-PrO)2P
MeCN
p-Tol
I
rt, 5 min
3b
4b
R
p-Tol
I
H
R
O
R = alkyl, aryl
Entry
Aldehyde
Product
Base
Yield (%)
Z/E
O–
S+
H
O
1
2
DBU
TBD
85
86
94:6
94:6
p-Tol
I
7
9
8
O–
H
S+
3
4
DBU
TBD
78
71
77:23
95:5
O
p-Tol
I
10
O–
S+
H
O
O
5
6
DBU
TBD
81
85
90:10
Z only
O
p-Tol
I
11
12
O–
S+
H
H
7
8
DBU
TBD
94
83
Z only
Z only
O
O
p-Tol
I
I
13
14
16
18
O–
S+
9a
DBU
TBD
30
27
83:17
Z only
p-Tol
10a
Me
Me
15
17
O–
H
S+
11
12
DBU
TBD
50
49
67:33
67:33
p-Tol
O
H
I
O–
S+
13
14
DBU
TBD
76
55
71:29
71:29
O
p-Tol
I
19
21
20
15
16
DBU
TBD
n.r.
n.r.
–
–
–
O
a Recovery of 15.
In conclusion, the stereoselective synthesis of α-iodo-
vinyl sulfoxides became possible by a one-pot iodination–
HWE protocol employing sulfinyl phosphonate, iodine, and
aldehyde. The resulting α-iodovinyl sulfoxides serve as
potential precursors for the preparation of trisubstituted
olefins, by subsequent coupling and sulfoxide–lithium
exchange. Further studies on applications are in progress
in our group.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
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Synlett
Acknowledgment
sumably due to the steric hindrance around the phosphorus
atom. Therefore, a thermodynamically controlled product is
preferably obtained. For related examples see: (a) Nagaoka, H.;
Kishi, Y. Tetrahedron 1981, 37, 3873. (b) Boschelli, D.; Takemasa,
T.; Nishitani, Y.; Masamune, S. Tetrahedron Lett. 1985, 26, 5239.
(11) See references related to anisotropic effect of the sulfinyl group:
(a) Pritchard, J. G.; Lauterbur, P. C. J. Am. Chem. Soc. 1961, 83,
2105. (b) Tanaka, S.; Sugihara, Y.; Sakamoto, A.; Ishii, A.;
Nakayama, J. Heteroatom Chem. 2003, 14, 587; and references
cited therein.
This work was supported by a Grant-in-Aid for Specially Promoted
Research (No.23000006 and No.15K13690) from JSPS.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561654.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(12) For related examples of the NMR analyses of tri- or tetrasubsti-
tuted α-iodovinyl sulfoxide, see: (a) Satoh, T.; Takano, K.; Ota,
H.; Someya, H.; Matsuda, K.; Koyama, M. Tetrahedron 1998, 54,
5557. (b) Fernández de la Pradilla, R.; Viso, A.; Castro, S.;
Fernández, J.; Manzano, P.; Tortosa, M. Tetrahedron 2004, 60,
8171; and references cited therein.
(13) One-pot iodination and HWE reaction was hinted by:
(a) Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 3064.
(b) Shibahara, S.; Fujino, M.; Tashiro, Y.; Okamoto, N.; Esumi, T.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Synthesis 2009, 2935.
(14) This reaction is exothermic, therefore, the reaction was con-
ducted in water bath for the large-scale reaction.
(15) Typical Procedure of One-Pot Iodination–HWE Reaction
In a two-necked round-bottomed flask was placed LiCl (44.7
mg, 0.314 mmol), to which a solution of sulfinyl-phosphonate
3b (100 mg, 0.314 mmol) in MeCN (1 mL) and TBD (87.4 mg,
0.628 mmol) or DBU (94.0 μL, 0.628 mmol) was added succes-
sively at room temperature. The mixture was stirred, and I2
(solid, 79.7 mg, 0.314 mmol) was added in several portions. The
mixture turned into an orange color solution. After stirring for
10 min, a solution of benzaldehyde (9, 22.2 mg, 0.209 mmol) in
MeCN (1 mL) was added slowly, and the stirring was continued
for 5 min at room temperature. The reaction was quenched by
adding 10% Na2S2O3 aqueous solution, the products were
extracted with EtOAc (3×), and the combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatogra-
phy (hexane–EtOAc = 2:1) to obtain 10 in 71% yield (Z/E = 95:5,
TBD) or 78% yield (Z/E = 77:23, DBU). Recrystallization (EtOAc–
hexane = 2:1) gave pure (Z)-10 as colorless needles.
References and Notes
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(d) Paley, R. S.; Weers, H. L.; Fernández, P. Tetrahedron Lett.
1995, 36, 3605. (e) Satoh, T.; Takano, K.; Someya, H.; Matsuda, K.
Tetrahedron Lett. 1995, 36, 7097. (f) Mikolajczyk, M.; Krysiak, J.
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Analytical Data for (Z)-10: Rf = 0.74 (hexane–EtOAc = 2:3); mp
84–86 °C. 1H NMR (600 MHz, CDCl3): δ = 2.41 (s, 3 H), 7.31 (d, 2
H, J = 8.1 Hz), 7.41–7.42 (m, 3 H), 7.60 (d, 2 H, J = 8.1 Hz), 7.77
(dd, 2 H, J = 6.5, 2.8 Hz), 8.16 (s, 1 H). 13C NMR (150 MHz, CDCl3):
δ = 21.5, 110.3, 126.0, 128.4, 129.2, 129.9, 130.0, 134.1, 138.9,
139.8, 142.3. IR (neat): 3052, 3023, 2973, 2920, 2865, 2360,
2342, 1593, 1491, 1445, 1397, 1266, 1178, 1084, 1059, 925,
872, 808, 749, 692 cm–1. [α]D20 +22.3 (c 1.11, CHCl3). HRMS (ESI-
TOF): m/z calcd for C15H14IOS [M + H]+: 368.9805; found:
368.9807. Anal. Calcd for C15H13IOS: C, 48.93; H, 3.56; S, 8.71.
Found: C, 48.96; H, 3.53; S, 8.52.
(6) Mikolajczyk, M.; Midura, W.; Grzejszczak, S.; Zatorski, A.;
Chefczynska, A. J. Org. Chem. 1978, 43, 473.
(7) The iodination was quenched by adding H2O. Quenching by aq
10% Na2S2O3 gave only the starting material 3a,b, though the
full conversion of the starting material and generation of
desired product 4a,b was confirmed by TLC analysis.
(8) Aldehyde 5 was used for the optimization study in the context
of our study on modular synthesis of planar chiral carba-para-
cyclophanes. For the synthesis of 5: Claus R. E., Schreiber S. L.;
Org. Synth.; 1986, 64: 150; see also ref. 4.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(16) Attempt for the reaction with acetophenone also failed, result-
ing in the formation of many unidentified byproducts.
(17) (a) Gilman, H.; Eidt, S. H. J. Am. Chem. Soc. 1956, 78, 3848.
(b) Durst, T.; LeBelle, M. J.; Van den Elzen, R.; Tin, K. C. Can. J.
Chem. 1974, 52, 761.
(10) Use of a bulky phosphonate tends to increase the Z selectivity.
This fact suggests that formation of the oxaphosphetane inter-
mediate and/or elimination of the phosphate become slow pre-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E